Lecture 14 - antipsychotics for schizophrenia

Question 1

what are the amine transmitters in CNS?

Answer 1

1. noradrenaline
2. dopamine
3. serotonin
4. acetylcholine

Question 2

how is noradrenaline inactivated?

Answer 2

by neuronal re-uptake or metabolism

Question 3

what metabolises noradrenaline?

Answer 3

1. monoamine oxidase (MAO)
2. aldehyde reductase
3. catechol-o-methyl-transferase (COMT)

Question 4

function of alpha1 (Gq) noradrenergic receptors

Answer 4

widely distributed and involved in motor control, cognition and fear.

Question 5

function of alpha2 (Gi) noradrenergic receptors?

Answer 5

involved with regulation of blood pressure, sedation and analgesia

Question 6

function of beta 1 (Gs) noradrenergic receptors?

Answer 6

in cortex, striatum and hippocampus contribute to long term effects of antidepressants.

Question 7

how is noradrenaline released?

Answer 7

‘diffusely’ rather than specific synapses

Question 8

characteristics for dopamine

Answer 8

involved in several common disorders including schizophrenia and its distribution is more restricted than noradrenaline

Question 9

where is dopamine highest in?

Answer 9

striatum forming parts of extrapyramidal motor system which is involved in coordination of movement.

Question 10

functional aspects of nigrostriatal pathway for dopamine

Answer 10

has cell bodies on substantia nigra for fine motor control

Question 11

functional aspects of mesocortical and mesolimbic pathway for dopamine

Answer 11

pathway distribution leads to stereotypical behaviour. also involved in pleasure and reward related to motivation

Question 12

functional aspect of tuberohypophyseal pathway for dopamine

Answer 12

has cell bodies in hypothalamus and involved in secretion of some hormones like prolactin

Question 13

how is dopamine terminated?

Answer 13

by enzymes COMT and MAO which are found both extracellularly and intracellularly and by action of re-uptake transporters.

Question 14

what is rate limiting enzymes for dopamine?

Answer 14

tyrosine hydroxylase

Question 15

structures for dopamine and noradrenaline?

Answer 15

they have similar structures so receptors structure that it binds to is also similar. makes it difficult when finding highly selective drugs

Question 16

what metabolite products are measured in a blood sample?

Answer 16

DOPAC and HVA

Question 17

function of D1,D5 dopamine receptors

Answer 17

• Gs coupled receptors so stimulate adenylyl cyclase to increase production of cAMP, PKA.
• D1 has decreased activity in mesocortical contributing to -ve symptoms

Question 18

functions of D2,D3 and D4 receptors

Answer 18

• Gi coupled receptors so inhibit adenylyl cyclase. activates K+ channels and inhibits Ca2+ channels through GABAa receptors.
• opposes effects of D1 receptor activation

Question 19

D2 action

Answer 19

increases activity in mesolimbic system causing +ve symptoms and is found in pituitary. more pharmacologically important.

Question 20

amphetamine action

Answer 20

accumulates in vesicles, noradrenaline increases in cytosol so transporters work in revere by releasing noradrenaline to increase signalling and activation of receptors.

Question 21

cocaine action

Answer 21

inhibits transporter so neurotransmitter is not effectively taken back up so signalling activation is for longer

Question 22

what are the positive symptoms for schizophrenia?

Answer 22

• hallucinations, delusions, thought disorders, defects in selective attention
• most prevalent in the young
• D2 receptors implicated

Question 23

what are the negative symptoms for schizophrenia?

Answer 23

• blunting of emotions, withdrawal from social contacts, flattening of emotional responses, anhedonia
• prevalent in elderly and prognosis is worse
• D1 receptors implicated

Question 24

genetic causes of schizophrenia

Answer 24

found to have hereditary origin as a result of abnormalities which arise early in life and disrupt normal development of the brain

Question 25

environmental causes of schizophrenia

Answer 25

- consumption of cannabis and drugs that increase dopamine signalling. - ketamine gives rise to +ve symptoms - LSD produces hallucinations and other schizophrenia like symptoms

Question 26

how does mesolimbic pathway cause +ve symptoms?

Answer 26

in mesolimbic areas, NMDA hypofunction results in increased dopamine signalling because NMDA receptors are on inhibitory GABAergic interneurons

Question 27

how does mesocortical pathway cause -ve symptoms?

Answer 27

with cognitive impairment, NMDA receptor hypofunction reduced activity of dopaminergic neurons, causing -ve symptoms

Question 28

what does dopamine receptors in chemoreceptor zone cause?

Answer 28

nausea and vomiting where the zones lies outside the BBB, co-administration with D2 antagonists that cannot cross BBB used to alleviate side effects

Question 29

first generation antipsychotics (typical)

Answer 29

e.g. chlorpromazine and haloperidol - have unwanted side effects including motor disturbances (extrapyramidal effects) and prolactin secretion. - treat severe anxiety and violent patients

Question 30

second generation antipsychotics (atypical)

Answer 30

e.g. clozapine, risperidone - some have enhanced selectivity for D2 receptors and less extrapyramidal side effects. - more effective against -ve symptoms as well as +ve symptoms

Question 31

action of clozapine

Answer 31

has D1 and D2 selectivity but more antimuscarinic to reduce extrapyramidal effects as muscarinic receptor activation contributes to extrapyramidal effects.

Question 32

unwanted effects of antipsychotic drugs

Answer 32

- worst symptom is dyskinesia where there is uncontrolled muscle movements. - increased prolactin release - sedation, hypotension and weight gain - dry mouth and blurred vision